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Mechanobiology: A New Frontier in Biology
Article

Comparison of Linear vs. Cyclic RGD Pentapeptide Interactions with Integrin αvβ3 by Molecular Dynamics Simulations

by 1,2,3,†, 1,2,†, 1, 1 and 1,2,*
1
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
2
Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, South China University of Technology, Guangzhou 510006, China
3
Key Laboratory of Southern Subtropical Plant Diversity, Fairy Lake Botanical Garden, Shenzhen & Chinese Academy of Sciences, Shenzhen 518004, China
*
Author to whom correspondence should be addressed.
Na Li and Simei Qiu contributed equally to this work.
Academic Editors: Tae-Jin Kim and Youhua Tan
Biology 2021, 10(7), 688; https://doi.org/10.3390/biology10070688
Received: 31 May 2021 / Revised: 13 July 2021 / Accepted: 16 July 2021 / Published: 20 July 2021
(This article belongs to the Special Issue Mechanobiology)
The integrin αvβ3-RGD motif interaction plays a key role in the progression of malignant tumor. Although two typical cyclic and linear RGD short peptides have been widely used in tumor diagnosis and therapy, little is known about the internal dynamic mechanism for different configurations of RGD peptides with different affinities interacting with the integrin αvβ3. Our results showed that the cyclic RGD peptide had a more stable configuration in binding to integrins αvβ3, which depended on the higher binding energy and higher static electrical energy, especially in the interaction between AspRGD-MIDAS. The steered molecular dynamics simulation showed a stronger interaction for the cyclic RGD-integrin αvβ3 system than the linear one, with a larger dissociation force (average peak force) and more time to dissociate. Our findings provide insights into the dynamics of integrin αvβ3 interactions with linear and cyclic RGD ligands and offer some new therapeutic approaches for the design and development of novel antitumor drugs.
Integrin αvβ3 interacting with the short Arg-Gly-Asp (RGD) motif plays a critical role in the progression of several types of tumors. However, the effects of the RGD structure (cyclic or linear) with integrin αvβ3 at the atomic level remain poorly understood. Here, we performed association and dissociation dynamic simulations for integrin αvβ3 in complex with a linear or cyclic pentapeptide by steered molecular dynamics simulations. Compared with cyclic RGD, the linear RGD peptide triggers instability of the configurational changes, mainly resting with the RGD domain due to its flexibility. The main interaction energy between Mg2+ and cyclic RGD is much stronger than that of the linear RGD system by the well shield to lessen attacks by free water molecules. The force-dependent dissociation results show that it is easier for linear RGD peptides to leave the active site and much quicker than the cyclic RGD ligand, whereas it is harder to enter the appropriate active binding site in linear RGD. The Ser123-AspRGD bond may play a critical role in the allosteric pathway. Our findings provide insights into the dynamics of αvβ3 interactions with linear and cyclic RGD ligands and contribute to the application of RGD-based strategies in preclinical therapy. View Full-Text
Keywords: integrin αvβ3; RGD peptide; force-induced dissociation; molecular dynamics simulations integrin αvβ3; RGD peptide; force-induced dissociation; molecular dynamics simulations
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MDPI and ACS Style

Li, N.; Qiu, S.; Fang, Y.; Wu, J.; Li, Q. Comparison of Linear vs. Cyclic RGD Pentapeptide Interactions with Integrin αvβ3 by Molecular Dynamics Simulations. Biology 2021, 10, 688. https://doi.org/10.3390/biology10070688

AMA Style

Li N, Qiu S, Fang Y, Wu J, Li Q. Comparison of Linear vs. Cyclic RGD Pentapeptide Interactions with Integrin αvβ3 by Molecular Dynamics Simulations. Biology. 2021; 10(7):688. https://doi.org/10.3390/biology10070688

Chicago/Turabian Style

Li, Na, Simei Qiu, Ying Fang, Jianhua Wu, and Quhuan Li. 2021. "Comparison of Linear vs. Cyclic RGD Pentapeptide Interactions with Integrin αvβ3 by Molecular Dynamics Simulations" Biology 10, no. 7: 688. https://doi.org/10.3390/biology10070688

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